The invention relates to compounds the principal characteristics of which include inhibition of the acyl-coenzyme A: cholesterol acyltransferase (ACAT) enzyme activity, and to a method for the preparation of such compounds.
The acyl-coenzyme A: cholesterol O-acyltransferase (EC 2.3.1.26) (ACAT) enzyme is responsible for the catalysis of the intracellular esterification of cholesterol. ACAT is present in most tissues such as the intestine, liver, and arterial wall. The enzyme is assumed to be involved in numerous processes which underlie the development of atherosclerosis, absorption of dietary cholesterol, accumulation of cholesterol esters, hepatic secretion of cholesterol esters into the blood plasma in the form of VLDL cholesterol.
A number of substances of the urea type have been described to inhibit ACAT. We shall show several more, recent examples describing 1,3-disubstituted ureas as ACAT enzyme inhibitors. Patents EP 506532, FR 2674522, JP 93097802, U.S. Pat. No. 5,219,859 describe ureas containing indole derivatives in their molecules. A combination of aromatic and aliphatic moieties has been described in Patents EP 665216, JP 95258199. Introduction into the molecule of a 1,3-dioxolane ring has been reported in Bioorg. Med. Chem. Lett. 1995, 5(15): 1581.
Despite the fact, the some 1,3-disubstituted ureas of the similar structure have been described in U.S. Pat. No. 3,284,433 as anticoccidial agents and one compound of similar structure is mentioned in patent application EP 0709225 as color developing agent, 1,3-disubstituted ureas of the present invention have not been described in literature yet.
1,3-Disubstituted ureas of general formula I, 
wherein R1 is 2-fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,6-di(methylethyl)phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, 1-adamantyl, and R2 is nitro, and Xxe2x95x90O,
wherein R1 is 4-nitrophenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,6-di(methylethyl)phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, 1-adamantyl, and R2 is nitro, and Xxe2x95x90S;
and for R1 being 2,4-difluorophenyl, 2,3-dichlorophenyl, 2,6-dimethylphenyl, 2,6-di(methylethyl)-phenyl R2 is amino, and Xxe2x95x90O, S.
The method for the preparation of the above compounds according to this invention consists in reacting an isocyanate (as prepared in situ or as commercially available) with amine to give an urea the nitro group of which may subsequently be reduced to the amino group. Ureas prepared in this way show inhibitory effect on acyl-coenzyme A: cholesterol acyltransferase (ACAT).